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Sequential Activation of Poly(ADP-Ribose) Polymerase 1, Calpains, and Bax Is Essential in Apoptosis-Inducing Factor-Mediated Programmed Necrosis

Open access
Moubarak, Rana S., Yuste, Victor J., Artus, Cédric, Bouharrour, Aïda, Greer, Peter A., Menissier-de Murcia, Josiane, Susin, Santos A.·2007·Molecular and Cellular Biology

Abstract

Alkylating DNA damage induces a necrotic type of programmed cell death through the poly(ADP-ribose) polymerases (PARP) and apoptosis-inducing factor (AIF). Following PARP activation, AIF is released from mitochondria and translocates to the nucleus, where it causes chromatin condensation and DNA fragmentation. By employing a large panel of gene knockout cells, we identified and describe here two essential molecular links between PARP and AIF: calpains and Bax. Alkylating DNA damage initiated a p53-independent form of death involving PARP-1 but not PARP-2. Once activated, PARP-1 mediated mitochondrial AIF release and necrosis through a mechanism requiring calpains but not cathepsins or caspases. Importantly, single ablation of the proapoptotic Bcl-2 family member Bax, but not Bak, prevented both AIF release and alkylating DNA damage-induced death. Thus, Bax is indispensable for this type of necrosis. Our data also revealed that Bcl-2 regulates N-methyl-N'-nitro-N'-nitrosoguanidine-induced necrosis. Finally, we established the molecular ordering of PARP-1, calpains, Bax, and AIF activation, and we showed that AIF downregulation confers resistance to alkylating DNA damage-induced necrosis. Our data shed new light on the mechanisms regulating AIF-dependent necrosis and support the notion that, like apoptosis, necrosis could be a highly regulated cell death program.

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Crossref · 10.1128/mcb.02141-06

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Metadata

Authors
Moubarak, R. S., Yuste, V. J., Artus, C., Bouharrour, A., Greer, P. A., Menissier-de Murcia, J., & Susin, S. A.
Venue
Molecular and Cellular Biology
Published
2007-07-01
Volume
27
Issue
13
Pages
4844-4862
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
OpenAlex
W1988860478
Cited by
322
References
4
FWCI
12.33
Type
journal article
Language
en
Open access
green

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